OXIDATIVE STRESS INDUCED APOPTOSIS IN CARDIAC MYOCYTES

氧化应激诱导心肌细胞凋亡

• 批准号: 6536529
• 负责人: Douglas B Sawyer
• 金额: $ 11.41万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-15 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6536529
• 关键词: anthracyclines; apoptosis; calcium flux; cardiac myocytes; cardiotoxin; chelating agents; free radical oxygen; gene targeting; genetically modified animals; iron metabolism; laboratory mouse; manganese; myocardial infarction; nuclear factor kappa beta; oxidative stress; superoxide dismutase; superoxides; tissue /cell culture; transcription factor; xanthine oxidase

DESCRIPTION (Adapted from applicants' abstract) The applicant's long term career goal is to contribute at a basic level to our understanding of the molecular mechanisms of heart failure. His short term career objectives are: 1) to gain insight into and learn techniques available for the measurement and manipulation of reactive oxygen species (ROS) in living systems; 2) use various molecular biological techniques for the manipulation and measurement of transcriptional events in cultured myocytes; 3) and then use in vivo animal models of myocardial injury and transgenic animals to test hypotheses developed in culture systems. The candidate received his Ph.D. in 1990 studying lipid protein interactions using single channel electrophysiology, and has spent the last 5 years at Brigham and Women's Hospital completing my clinical training in internal medicine and cardiology. There he began to study the mechanisms of ROS mediated myocardial injury, specifically, programmed cell death. He recently moved to Boston Medical Center to continue these efforts. The particular interest of cardiology and medicine faculty there in ROS provides a fertile environment for him to develop his scientific ideas. The hypotheses he will test are that ROS, in particular superoxide anion and/or hydroxyl radicals, can trigger apoptosis in ventricular myocytes, and that myocytes are able to regulate their susceptibility to these species by transcriptional regulation of cytotoxic defense systems. Firstly, he will use cultured adult and neonatal rat ventricular myocytes to examine exactly which ROS can induce apoptosis in cultured myocytes. Secondly, he will examine whether preconditioning stimuli can increase activities of specific cytotoxic defense systems and in this way prevent ROS-mediated apoptosis in ventricular myocytes. Thirdly, using an adenovirus transfection system, he will study whether over-expression of superoxide dismutase or catalase can protect against ROS-Induced apoptosis in cardiac myocytes. Finally, he will examine whether transgenic mice over-expressing manganese-dependent superoxide dismutase have increased susceptibility to myocardial apoptosis after myocardial infarction.

描述 （摘自申请人摘要）申请人的长期职业目标是 在基础层面上帮助我们理解 心力衰竭的机制。 他的短期职业目标是：1） 深入了解和学习可用于测量的技术， 操纵活性氧（ROS）在生活系统; 2）使用 用于操作和测量的各种分子生物学技术 的转录事件在培养的心肌细胞; 3），然后在体内使用 心肌损伤的动物模型和转基因动物来检验假设 在文化体系中发展。 候选人获得了博士学位。1990年 使用单通道电生理学研究脂质蛋白相互作用， 在布里格姆妇女医院工作了5年， 内科和心脏病学的临床培训。 在那里，他开始 研究ROS介导的心肌损伤机制，具体而言， 程序性细胞死亡 他最近搬到波士顿医疗中心， 继续这些努力。 心脏病学和医学的特殊兴趣 ROS的教师为他提供了一个肥沃的环境来发展他的 科学理念 他将检验的假设是， 超氧阴离子和/或羟基自由基，可以引发细胞凋亡， 心室肌细胞，并且肌细胞能够调节它们的 通过细胞毒性的转录调节对这些物种的易感性 防御系统。 首先，他将使用培养的成年和新生大鼠 心室肌细胞以准确检查哪些活性氧可以诱导细胞凋亡 培养的心肌细胞 其次，他将研究预处理是否 刺激可以增加特定细胞毒性防御系统的活性， 这种方式防止ROS介导的心室肌细胞凋亡。 第三， 利用腺病毒转染系统，他将研究 超氧化物歧化酶或过氧化氢酶的过表达可以防止 ROS诱导的心肌细胞凋亡。 最后，他将研究是否 锰依赖性超氧化物歧化酶转基因小鼠 心肌细胞凋亡的易感性增加， 梗塞